Role of Genetic Testing in the Staging of Multiple Myeloma

Jatin Shah, MD: After the diagnosis of myeloma is made, the next step is to stage these patients. We typically think about staging in cancer to really help identify if it’s stage 1, 2, 3, or 4, traditionally in solid tumors, and to see if it’s a localized or a systemic process or localized or metastatic. Typically, we’ll use staging in solid tumors, or even in Non-Hodgkin’s lymphoma, for example, to help determine, really, the therapeutic choices that we’re going to do. So stage 1 patients may just get surgery alone. And if you’re a stage 2 or 3, you may get surgery plus or minus chemotherapy or radiation, or just chemotherapy alone for stage 4 patients, broadly speaking. That’s very different, and it also helps from a prognostic perspective, choosing a therapeutic option as well as a prognosis.

In myeloma we just have 3 stages—stage 1, 2, and 3. And we stage based on 2 simple tests—a beta-2 microglobulin and albumin, which are simple blood tests that we can use. And it’s much more helpful from, not a therapeutic perspective, but from a prognostic purpose. And so you can start using stage 1, 2, and 3 to help dictate which therapies you may or may not choose; but the main really goal of prognosis, and for long-term outcomes for these patients.

Now we’ve revised our ISS stage that we use now for staging and adding in genetic features, as well. In addition to the biological features, the beta-2 microglobulin and albumin, it’s important to really understand the disease biology as well. So we know that there’s a number of high-risk features or genetic mutations that we can see, which also will affect long-term outcome and prognosis. So it’s important to look at genetic testing both for FISH and cytogenetics, and now gene expression profiles, as well, to really identify various subsets of patients with different prognosis. And we’ve incorporated that now into our revised ISS stage, or the RISS, which was just recently published as well, looking at both traditional beta-2 microglobulin and albumin that we can measure in the blood, in addition to our genetic mutations as well.

The diagnosis of smoldering myeloma is based on having clonal plasma cells, or proliferation of plasma cells, without end-organ damage. That’s how we’ve classically defined smoldering myeloma; so, patients who have increased plasma cells in their bone marrow, paraprotein production, but no other evidence of end-organ damage. And that’s kind of globally how we looked at smoldering myeloma. So those are patients who did not have that CRAB criteria that we often talk about historically with elevations in calcium or kidney function, anemia or bone lesions. So, if you have no impact on the patient and the patient is otherwise asymptomatic, then we would call that smoldering myeloma, or MGUS.

Importantly, when you look at smoldering myeloma there’s various subsets of patients, including patients with high-risk smoldering myeloma, or low-risk smoldering myeloma. There’s a big difference in their progression-free survival. So, for example, patients with ultra-high—risk or high-risk smoldering myeloma will progress to active myeloma needing systemic therapy in the next 18 to 24 months versus patients with low risk may stay in that low-risk state and not progress to active myeloma for 9 to 10 years. And, so, if you can identify those patients who have a chance of progression in the next 1 to 2 years, you may want to consider early intervention in those patients.

Importantly, we want to target patients potentially for high-risk myeloma and see if we could intervene early in these patients as opposed for them to wait till have end-organ damage. And I think that’s an exciting field, trying to intervene patients early before they get those end-organ damage, and the effect on their quality of life before they get kidney failure and their boney lesions or their pathologic fractures.

However, that becomes quite controversial. There’s some data looking at lenalidomide and dexamethasone in patients with smoldering myeloma. The challenge with that dataset is that the way they define smoldering myeloma is very different than how we would classically define smoldering myeloma here in the US. They define smoldering myeloma in part based on various close cytometry measurements, which are not routinely done here in the US or globally. And, so, I think that even though if you look at the bottom line, there’s some activity with lenalidomide and dexamethasone in terms of delaying progression-free survival in smoldering myeloma. The way they define smoldering myeloma is different now than it was classically defined in that study. So I think that that’s very interesting data as a proof of concept. But I think much more research has to be done before we routinely recommend using lenalidomide and dexamethasone for smoldering myeloma patients.